CN112851603A - Preparation method of (3R) -tetrahydro-3-furanmethanamine - Google Patents
Preparation method of (3R) -tetrahydro-3-furanmethanamine Download PDFInfo
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- CN112851603A CN112851603A CN202110043921.6A CN202110043921A CN112851603A CN 112851603 A CN112851603 A CN 112851603A CN 202110043921 A CN202110043921 A CN 202110043921A CN 112851603 A CN112851603 A CN 112851603A
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- furanmethanamine
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- CINJIXGRSTYIHP-RXMQYKEDSA-N [(3r)-oxolan-3-yl]methanamine Chemical compound NC[C@H]1CCOC1 CINJIXGRSTYIHP-RXMQYKEDSA-N 0.000 title claims abstract description 34
- 238000002360 preparation method Methods 0.000 title claims abstract description 11
- 238000001914 filtration Methods 0.000 claims abstract description 40
- 150000003839 salts Chemical class 0.000 claims abstract description 39
- 239000003960 organic solvent Substances 0.000 claims abstract description 37
- 238000003756 stirring Methods 0.000 claims abstract description 29
- 239000007787 solid Substances 0.000 claims abstract description 26
- 238000000034 method Methods 0.000 claims abstract description 18
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 13
- 239000000706 filtrate Substances 0.000 claims abstract description 11
- 238000005406 washing Methods 0.000 claims abstract description 11
- 238000001953 recrystallisation Methods 0.000 claims abstract description 9
- 239000003513 alkali Substances 0.000 claims abstract description 5
- 239000000126 substance Substances 0.000 claims abstract description 5
- 230000001376 precipitating effect Effects 0.000 claims abstract description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 76
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 31
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 30
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 30
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 27
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 27
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 22
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 claims description 18
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims description 18
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims description 18
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 18
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 9
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 9
- 150000001298 alcohols Chemical class 0.000 claims description 9
- 150000002148 esters Chemical class 0.000 claims description 9
- 150000002170 ethers Chemical class 0.000 claims description 9
- 150000008282 halocarbons Chemical class 0.000 claims description 9
- 150000002576 ketones Chemical class 0.000 claims description 9
- YKYONYBAUNKHLG-UHFFFAOYSA-N n-Propyl acetate Natural products CCCOC(C)=O YKYONYBAUNKHLG-UHFFFAOYSA-N 0.000 claims description 9
- 229940090181 propyl acetate Drugs 0.000 claims description 9
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 claims description 9
- 239000002253 acid Substances 0.000 claims description 7
- AEDZKIACDBYJLQ-UHFFFAOYSA-N ethane-1,2-diol;hydrate Chemical compound O.OCCO AEDZKIACDBYJLQ-UHFFFAOYSA-N 0.000 claims description 3
- 238000006243 chemical reaction Methods 0.000 abstract description 25
- 238000009776 industrial production Methods 0.000 abstract description 4
- 235000019441 ethanol Nutrition 0.000 description 24
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 21
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 18
- 238000001816 cooling Methods 0.000 description 14
- 239000007788 liquid Substances 0.000 description 12
- 229940095064 tartrate Drugs 0.000 description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- 239000007864 aqueous solution Substances 0.000 description 7
- 238000001035 drying Methods 0.000 description 7
- 238000010438 heat treatment Methods 0.000 description 7
- 239000000047 product Substances 0.000 description 5
- 239000012043 crude product Substances 0.000 description 4
- 238000002425 crystallisation Methods 0.000 description 4
- 230000008025 crystallization Effects 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- IWYDHOAUDWTVEP-UHFFFAOYSA-N R-2-phenyl-2-hydroxyacetic acid Natural products OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 description 2
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- IWYDHOAUDWTVEP-UHFFFAOYSA-M mandelate Chemical compound [O-]C(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-M 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- BOTREHHXSQGWTR-UHFFFAOYSA-N oxolane-3-carboxylic acid Chemical compound OC(=O)C1CCOC1 BOTREHHXSQGWTR-UHFFFAOYSA-N 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 239000012265 solid product Substances 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- QBYIENPQHBMVBV-HFEGYEGKSA-N (2R)-2-hydroxy-2-phenylacetic acid Chemical compound O[C@@H](C(O)=O)c1ccccc1.O[C@@H](C(O)=O)c1ccccc1 QBYIENPQHBMVBV-HFEGYEGKSA-N 0.000 description 1
- YONLFQNRGZXBBF-ZIAGYGMSSA-N (2r,3r)-2,3-dibenzoyloxybutanedioic acid Chemical compound O([C@@H](C(=O)O)[C@@H](OC(=O)C=1C=CC=CC=1)C(O)=O)C(=O)C1=CC=CC=C1 YONLFQNRGZXBBF-ZIAGYGMSSA-N 0.000 description 1
- IWYDHOAUDWTVEP-SSDOTTSWSA-N (R)-mandelic acid Chemical compound OC(=O)[C@H](O)C1=CC=CC=C1 IWYDHOAUDWTVEP-SSDOTTSWSA-N 0.000 description 1
- MIOPJNTWMNEORI-GMSGAONNSA-N (S)-camphorsulfonic acid Chemical compound C1C[C@@]2(CS(O)(=O)=O)C(=O)C[C@@H]1C2(C)C MIOPJNTWMNEORI-GMSGAONNSA-N 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000012496 blank sample Substances 0.000 description 1
- 238000003889 chemical engineering Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 229960002510 mandelic acid Drugs 0.000 description 1
- CINJIXGRSTYIHP-UHFFFAOYSA-N oxolan-3-ylmethanamine Chemical compound NCC1CCOC1 CINJIXGRSTYIHP-UHFFFAOYSA-N 0.000 description 1
- 238000002953 preparative HPLC Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/04—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D307/10—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D307/14—Radicals substituted by nitrogen atoms not forming part of a nitro radical
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B57/00—Separation of optically-active compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
The invention discloses a preparation method of (3R) -tetrahydro-3-furanmethanamine, which comprises the following steps: dissolving racemic (+/-) -tetrahydro-3-furanmethanamine in a first organic solvent, adding a resolving agent, stirring, precipitating a solid, and filtering the solid to obtain a salt; dissolving the salt in a second organic solvent for recrystallization to obtain purified salt; dissolving the purified salt in a third organic solvent, adding alkali, sequentially stirring, filtering, washing, dissolving, filtering to remove insoluble substances, and concentrating the filtrate to dryness to obtain (3R) -tetrahydro-3-furanmethanamine. The preparation method of (3R) -tetrahydro-3-furanmethanamine provided by the invention has the advantages of simple process, easy post-treatment, mild condition, low reaction cost, high yield, good purity and suitability for industrial production.
Description
Technical Field
The invention relates to the technical field of medicines, chemical engineering and materials, in particular to a preparation method of (3R) -tetrahydro-3-furanmethanamine.
Background
The (3R) -tetrahydro-3-furanmethanamine is an important medical intermediate, the tetrahydrofuran ring can effectively increase the hydrophilicity of the medicine, and the amino group is taken as a derivative group, can be butted with multiple multifunctional groups, and can be widely used for synthesis and conversion in the fields of medicine and materials.
The synthesis of chiral tetrahydro-3-furanmethanamine is less reported, and US patent US2014/275082 reports the synthetic route: racemic tetrahydro-3-furancarboxylic acid is adopted, chiral acid is obtained through chiral preparative HPLC, and then (3R) -tetrahydro-3-furanmethanamine can be synthesized through 4 steps of reaction. The specific synthetic route is as follows:
the main problems of this route are that 1) the starting material tetrahydro-3-furancarboxylic acid is not a commercial reagent and is relatively expensive; 2) chiral sources need to be prepared by low efficiency SFC; 3) highly toxic sodium azide was used. The synthesis efficiency of the route is low, and large-scale industrial production is difficult.
Disclosure of Invention
In view of the defects in the preparation of (3R) -tetrahydro-3-furanmethanamine, the invention provides the preparation method of (3R) -tetrahydro-3-furanmethanamine, and the preparation method has the advantages of simple process, easy post-treatment, mild conditions, low reaction cost, high yield and good purity, and is suitable for industrial production.
In order to achieve the purpose, the invention adopts the following technical scheme:
a preparation method of (3R) -tetrahydro-3-furanmethanamine comprises the following steps:
dissolving racemic (+/-) -tetrahydro-3-furanmethanamine in a first organic solvent, adding a resolving agent, stirring, precipitating a solid, and filtering the solid to obtain a salt;
dissolving the salt in a second organic solvent for recrystallization to obtain purified salt;
dissolving the purified salt in a third organic solvent, adding alkali, sequentially stirring, filtering, washing, dissolving, filtering to remove insoluble substances, and concentrating the filtrate to dryness to obtain (3R) -tetrahydro-3-furanmethanamine.
According to one aspect of the present invention, the first organic solvent is one or a combination of any two or more of alcohols, esters, ketones, ethers, halogenated hydrocarbons and water.
In accordance with one aspect of the invention, the resolving agent is a chiral acid.
According to one aspect of the present invention, the second organic solvent is one or a combination of any two or more of alcohols, esters, ketones, ethers, halogenated hydrocarbons and water.
According to one aspect of the present invention, the third organic solvent is one or a combination of any two or more of alcohols, esters, ketones, ethers, halogenated hydrocarbons and water.
According to one aspect of the present invention, the first organic solvent is one or a combination of any two or more of methanol, ethanol, n-propanol, isopropanol, ethyl acetate, propyl acetate, acetone, butanone, dioxane, 2-methyl-tetrahydrofuran, dichloromethane, chlorobenzene, ethylene glycol dimethyl ether, and water.
According to an aspect of the present invention, the second organic solvent is one or a combination of any two or more of methanol, ethanol, n-propanol, isopropanol, water, ethyl acetate, propyl acetate, acetone, butanone, dioxane, 2-methyl-tetrahydrofuran, dichloromethane, chlorobenzene, and ethylene glycol dimethyl ether.
According to an aspect of the present invention, the third organic solvent is one or a combination of any two or more of methanol, ethanol, n-propanol, isopropanol, water, ethyl acetate, propyl acetate, acetone, butanone, dioxane, 2-methyl-tetrahydrofuran, dichloromethane, chlorobenzene, and ethylene glycol dimethyl ether.
According to one aspect of the invention, the number of recrystallizations is 2.
According to one aspect of the invention, the temperature during which the resolving agent is added and stirred to precipitate the solid is between 0 ℃ and 100 ℃.
Compared with the prior art, the invention has the following advantages and beneficial effects:
(1) the method adopts a commercial reagent of racemic (+/-) -tetrahydro-3-furanmethanamine as a raw material, and has low price;
(2) the raw materials are cheap and easy to obtain, and the method has mild splitting process conditions and easy control, and is suitable for industrial production;
(3) the chiral purity of the prepared (3R) -tetrahydro-3-furanmethanamine is high and can reach more than 97.1 percent.
Drawings
In order to more clearly illustrate the technical solutions in the embodiments of the present invention, the drawings needed to be used in the embodiments will be briefly described below, and it is obvious that the drawings in the following description are only some embodiments of the present invention, and it is obvious for those skilled in the art that other drawings can be obtained according to these drawings without creative efforts.
FIG. 1 is a high performance liquid chromatogram of (3R) -tetrahydro-3-furanmethanamine obtained in example 1 of the present invention;
FIG. 2 is a high performance liquid chromatogram of a racemate control of (3R) -tetrahydro-3-furanmethanamine in example 1 of the present invention;
FIG. 3 is a high performance liquid chromatogram of a blank sample of (3R) -tetrahydro-3-furanmethanamine in example 1 of the present invention;
FIG. 4 is a gas chromatogram of (3R) -tetrahydro-3-furanmethanamine obtained in example 1 of the present invention.
Detailed Description
The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the drawings in the embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
A preparation method of (3R) -tetrahydro-3-furanmethanamine comprises the following steps:
(1) dissolving racemic (+/-) -tetrahydro-3-furanmethanamine in a first organic solvent, adding a resolving agent, stirring, precipitating a solid, and filtering the solid to obtain a salt. The first organic solvent is used for dissolving racemic (+/-) -tetrahydro-3-furanmethanamine and a resolving agent, and ensuring that the racemic (+/-) -tetrahydro-3-furanmethanamine and the resolving agent react to generate corresponding salt; the first organic solvent can be one or the combination of more than two of alcohols, esters, ketones, ethers, halogenated hydrocarbons and water; the first organic solvent can adopt one or the combination of more than two of methanol, ethanol, n-propanol, isopropanol, ethyl acetate, propyl acetate, acetone, butanone, dioxane, 2-methyl-tetrahydrofuran, dichloromethane, chlorobenzene, ethylene glycol dimethyl ether and water; the first organic solvent is preferably a combination of ethanol and water; the resolving agent is chiral acid, and the chiral acid can be any one of tartaric acid and derivatives thereof, mandelic acid, camphorsulfonic acid, malic acid and arginine; the temperature of the process of adding the resolving agent and separating out the solid after stirring is 0-100 ℃; the preferable temperature of the process of adding the resolving agent and separating out the solid after stirring is 10-30 ℃; the mass of the first organic solvent is 0-50 times of the mass of the crude product; the mass of the first organic solvent is preferably 2-6 times of the mass of the crude product; the mass of the chiral acid is 0-20 times of that of the crude product; the mass of the chiral acid is preferably 0.5 to 2 times of the mass of the crude product.
(2) And dissolving the salt in a second organic solvent for recrystallization to obtain the purified salt. Wherein the second organic solvent is used in the recrystallization of the salt; the second organic solvent can be selected from one or the combination of more than two of alcohols, esters, ketones, ethers, halogenated hydrocarbons and water; the second organic solvent can adopt one or the combination of more than two of methanol, ethanol, n-propanol, isopropanol, water, ethyl acetate, propyl acetate, acetone, butanone, dioxane, 2-methyl-tetrahydrofuran, dichloromethane, chlorobenzene and ethylene glycol dimethyl ether; the more the number of said recrystallizations, the higher the purity but the lower the yield. Therefore, in order to secure purity and yield, the number of recrystallization is preferably 2.
(3) Dissolving the purified salt in a third organic solvent, adding alkali, sequentially stirring, filtering, washing, dissolving, filtering to remove insoluble substances, and concentrating the filtrate to dryness to obtain (3R) -tetrahydro-3-furanmethanamine. Wherein the third organic solvent is used for dissolving the purified salt, ensuring that the purified salt and the alkali react in the third organic solvent; the third organic solvent can be one or the combination of more than two of alcohols, esters, ketones, ethers, halogenated hydrocarbons and water; the third organic solvent can adopt one or the combination of more than two of methanol, ethanol, n-propanol, isopropanol, water, ethyl acetate, propyl acetate, acetone, butanone, dioxane, 2-methyl-tetrahydrofuran, dichloromethane, chlorobenzene and ethylene glycol dimethyl ether.
Example 1
At 30 ℃, 30mL of absolute ethanol and 6mL of water are added into a No. 1 reaction bottle of 50mL, 3.0g of racemic (+/-) -tetrahydro-3-furanmethanamine is added, 4.4g L-tartaric acid is added, stirring is carried out for 30 minutes, a large amount of solid is separated out, and 7.7g of salt with the chiral purity of 39.7 percent is obtained by filtration.
Adding 7.7g of salt into a No. 2 reaction bottle with the volume of 50mL, adding 18mL of ethanol and 3.7mL of water, heating until the salt is dissolved, stirring for 30 minutes, slowly cooling for crystallization for 16 hours, slowly cooling to 30 ℃, filtering, draining to obtain 3.8g of a solid product, and drying at the temperature of 50 ℃ to obtain 3.1g of tartrate as a white solid.
3.1g of the prepared tartrate and 22mL of anhydrous ethanol are sequentially added into a No. 3 reaction bottle of 50mL at the temperature of 30 ℃, the temperature is controlled to be 25-35 ℃, 2.9g of NaOH aqueous solution of 30% w/w is slowly dripped, and after the dripping is finished, the mixture is stirred for 2 hours. Filtration, washing with 3mL of ethanol, concentration under reduced pressure to dryness, then addition of 3mL of THF (tetrahydrofuran) dissolved, filtration of insoluble substances, filtrate under reduced pressure to dryness, 1.25g of light yellow liquid. The obtained light yellow liquid is analyzed by high performance liquid chromatography, as shown in fig. 1, fig. 2 and fig. 3, the obtained light yellow liquid is (3R) -tetrahydro-3-furanmethanamine, and the related data of the corresponding peaks in fig. 1 are shown in the following table 1:
table 1:
as can be seen from the table, the chiral purity of (3R) -tetrahydro-3-furanmethanamine obtained in this example was 99.2%.
FIG. 4 is a gas chromatogram of the prepared (3R) -tetrahydro-3-furanmethanamine, and the corresponding relevant data of FIG. 4 are shown in the following Table 2:
table 2:
as is clear from Table 1, the GC purity of (3R) -tetrahydro-3-furanmethanamine obtained in this example was 98.3%.
Example 2
40mL of absolute ethanol was added to a 50mL reaction flask No. 1 at 11 ℃, 3.0g of racemic (. + -.) -tetrahydro-3-furanmethanamine was added, and 4.4g L-tartaric acid was added and stirred for 30min, and a large amount of solid was precipitated. Filtration gave 8.9g of salt with chiral purity of 26.7%.
Adding 7.7g of salt into a No. 2 reaction bottle with the volume of 50mL, adding 18mL of ethanol and 3.7mL of water, heating until the salt is dissolved, stirring for 30min, slowly cooling for crystallization for 16h, slowly cooling to 11 ℃, filtering, draining to obtain 4.8g of solid product, and drying at the temperature of 50 ℃ to obtain 4.3g of tartrate as a white solid.
And (2) adding 6.2g of tartrate and 22mL of absolute ethyl alcohol into a No. 3 reaction bottle of 50mL in sequence at the temperature of 11 ℃, controlling the temperature to be 25-35 ℃, slowly dropwise adding 4.0g of 30% w/w NaOH aqueous solution, and stirring for 2 hours after dropwise adding is finished. Filtration, washing with 3mL of ethanol, concentration under reduced pressure to dryness, then addition of 3mL of THF (tetrahydrofuran) to dissolve, filtration of insoluble matter, concentration of filtrate under reduced pressure to dryness, yielded 2.3g of a pale yellow liquid, chiral purity: 97.0%, GC purity: 97.1 percent.
Example 3
40mL of ethyl acetate was added to a 50mL reaction flask No. 1 at 25 ℃, 3g of racemic (. + -.) -tetrahydro-3-furanmethanamine was added, 4.4g L-tartaric acid was added thereto, and stirring was carried out for 30min, whereby a large amount of solid was precipitated. Filtering to obtain salt.
And adding the obtained salt into a No. 2 reaction bottle of 50mL, adding 18mL of ethanol and 3.7mL of water, heating until the salt is dissolved, stirring for 30min, slowly cooling for crystallization for 16h, slowly cooling to 25 ℃, filtering, draining to obtain 7.8 g of a white wet product, and drying at 50 ℃ to obtain 6.2g of tartrate as a white solid.
And (2) sequentially adding 6.2g of tartrate and 22mL of absolute ethyl alcohol into a No. 3 reaction bottle of 50mL at 25 ℃, controlling the temperature to be 25-35 ℃, slowly dropwise adding 4.0g of 30% w/w NaOH aqueous solution, and stirring for 2 hours after dropwise adding is finished. Filtration, washing with 3mL of ethanol, concentration under reduced pressure to dryness, then addition of 3mL of THF (tetrahydrofuran) to dissolve, filtration of insoluble matter, concentration of filtrate under reduced pressure to dryness, yielded 2.3g of a pale yellow liquid, chiral purity: 97.0%, GC purity: 97.1 percent.
Example 4
At 30 ℃, 30mL of absolute ethanol and 6mL of water are added into a No. 1 reaction bottle of 50mL, 3.0g of racemic (+/-) -tetrahydro-3-furanmethanamine is added, 6.8g of (-) -dibenzoyl tartaric acid is added, and the mixture is stirred for 30 minutes, so that a large amount of solid is separated out. Filtration gave 9.5g of salt.
Adding 9.5g of salt into a No. 2 reaction bottle with the volume of 50mL, adding 18mL of ethanol and 3.7mL of water, heating until the salt is dissolved, stirring for 30 minutes, slowly cooling for crystallization for 16 hours, slowly cooling to 30 ℃, filtering, draining to obtain 5.8g of a fixed product, and drying at the temperature of 50 ℃ to obtain 4.5g of tartrate as a white solid.
Adding 4.5g of tartrate and 22mL of absolute ethyl alcohol into a No. 3 reaction bottle of 50mL in sequence at the temperature of 30 ℃, controlling the temperature to be 25-35 ℃, slowly dropwise adding 2.9g of 30% w/w sodium hydroxide aqueous solution, and stirring for 2 hours after dropwise adding is finished. Filtration, washing with 3mL of ethanol, concentration to dryness under reduced pressure, then dissolution with 3mL of THF (tetrahydrofuran), filtration of insoluble matter, concentration of filtrate to dryness under reduced pressure, gave 1.34g of a pale yellow liquid, chiral purity: 98.8%, GC purity: 97.2 percent.
Example 5
At 25 ℃, 30mL of absolute ethyl alcohol and 6mL of water are added into a No. 1 reaction bottle of 50mL, 3.0g of racemic (+/-) -tetrahydro-3-furanmethanamine is added, 4.6g of (-) -mandelic acid is added, and stirring is carried out for 30 minutes, so that a large amount of solid is separated out. Filtration gave 9.5g of salt.
Adding the obtained 9.5g of salt into a No. 2 reaction bottle of 50mL, adding 18mL of ethanol and 3.7mL of water, heating until the salt is dissolved, stirring for 30 minutes, slowly cooling and crystallizing for 16 hours, slowly cooling to 25 ℃, filtering, draining to obtain 4.8g of a fixed product, and drying at 50 ℃ to obtain 3.2g of mandelate as a white solid.
Adding 3.2g of mandelate and 22mL of anhydrous ethanol into a No. 3 reaction bottle of 50mL in sequence at 25 ℃, controlling the temperature to be 25-35 ℃, slowly dropwise adding 2.9g of 30% w/w sodium hydroxide aqueous solution, and stirring for 2 hours after dropwise adding is finished. Filtration, washing with 3mL of ethanol, concentration under reduced pressure to dryness, then addition of 3mL of THF (tetrahydrofuran) to dissolve, filtration of insoluble matter, concentration of filtrate under reduced pressure to dryness, gave 0.86g of a pale yellow liquid, chiral purity: 97.2%, GC purity: 97.4 percent.
Example 6
To a 50mL reaction flask # 1, 30mL of absolute ethanol and 6mL of water were added at 35 ℃, 3.0g of racemic (. + -.) -tetrahydro-3-furanmethanamine and 4.4g L-tartaric acid were added, and stirring was carried out for 30 minutes, whereby a large amount of solid was precipitated. Filtration gave 7.7g of salt with a chiral purity of 39.7%.
Adding the obtained 7.7g of salt into a No. 2 reaction bottle of 50mL, adding 18mL of isopropanol and 3.7mL of water, heating to dissolve, stirring for 30 minutes, slowly cooling to crystallize for 16 hours, slowly cooling to 35 ℃, filtering, draining to obtain 3.7g of fixed product, and drying at 50 ℃ to obtain 2.9g of tartrate as a white solid.
Adding 2.9g of tartrate and 22mL of absolute ethyl alcohol into a No. 3 reaction bottle of 50mL in sequence at the temperature of 35 ℃, controlling the temperature to be 25-35 ℃, slowly dropwise adding 2.9g of 30% w/w NaOH aqueous solution, and stirring for 2 hours after dropwise adding is finished. Filtration, washing with 3mL of ethanol, concentration under reduced pressure to dryness, then addition of 3mL of THF (tetrahydrofuran) to dissolve, filtration of insoluble matter, concentration of filtrate under reduced pressure to dryness, gave 1.05g of a pale yellow liquid, chiral purity: 97.2%, GC purity: 98.3 percent.
Example 7
To a 50mL reaction flask No. 1, 30mL of absolute ethanol and 6mL of water were added at 25 ℃, 3.0g of racemic (. + -.) -tetrahydro-3-furanmethanamine and 4.4g L-tartaric acid were added, and stirring was carried out for 30 minutes, whereby a large amount of solid was precipitated. Filtration gave 7.7g of salt with a chiral purity of 39.7%.
Adding the obtained 7.7g of salt into a No. 2 reaction bottle of 50mL, adding 18mL of isopropanol and 3.7mL of water, heating to dissolve, stirring for 30 minutes, slowly cooling to crystallize for 16 hours, slowly cooling to 25 ℃, filtering, draining to obtain 3.7g of fixed product, and drying at 50 ℃ to obtain 2.9g of tartrate as a white solid.
Adding 2.9g of tartrate and 22mL of absolute ethyl alcohol into a No. 3 reaction bottle of 50mL in sequence at 25 ℃, controlling the temperature to be 25-35 ℃, slowly dropwise adding 2.9g of 30% w/w NaOH aqueous solution, and stirring for 2 hours after dropwise adding is finished. Filtration, washing with 3mL of methanol, concentration to dryness under reduced pressure, then dissolution with 3mL of THF (tetrahydrofuran), filtration of insoluble matter, concentration of filtrate to dryness under reduced pressure, gave 1.05g of a pale yellow liquid, chiral purity: 97.1%, GC purity: 98.1 percent.
The above description is only an embodiment of the present invention, but the scope of the present invention is not limited thereto, and any changes or substitutions that can be easily conceived by those skilled in the art within the technical scope of the present invention disclosed herein are intended to be covered by the scope of the present invention. Therefore, the protection scope of the present invention shall be subject to the protection scope of the appended claims.
Claims (10)
1. A preparation method of (3R) -tetrahydro-3-furanmethanamine is characterized in that: the method comprises the following steps:
dissolving racemic (+/-) -tetrahydro-3-furanmethanamine in a first organic solvent, adding a resolving agent, stirring, precipitating a solid, and filtering the solid to obtain a salt;
dissolving the salt in a second organic solvent for recrystallization to obtain purified salt;
dissolving the purified salt in a third organic solvent, adding alkali, sequentially stirring, filtering, washing, dissolving, filtering to remove insoluble substances, and concentrating the filtrate to dryness to obtain (3R) -tetrahydro-3-furanmethanamine.
2. The process for producing (3R) -tetrahydro-3-furanmethanamine according to claim 1, wherein: the first organic solvent is one or the combination of more than two of alcohols, esters, ketones, ethers, halogenated hydrocarbons and water.
3. The process for producing (3R) -tetrahydro-3-furanmethanamine according to claim 1, wherein: the resolving agent is chiral acid.
4. The process for producing (3R) -tetrahydro-3-furanmethanamine according to claim 1, wherein: the second organic solvent is one or the combination of more than two of alcohols, esters, ketones, ethers, halogenated hydrocarbons and water.
5. The process for producing (3R) -tetrahydro-3-furanmethanamine according to claim 1, wherein: the third organic solvent is one or the combination of more than two of alcohols, esters, ketones, ethers, halogenated hydrocarbons and water.
6. The process for producing (3R) -tetrahydro-3-furanmethanamine according to claim 2, wherein: the first organic solvent is one or the combination of more than two of methanol, ethanol, n-propanol, isopropanol, ethyl acetate, propyl acetate, acetone, butanone, dioxane, 2-methyl-tetrahydrofuran, dichloromethane, chlorobenzene, ethylene glycol dimethyl ether and water.
7. The process for producing (3R) -tetrahydro-3-furanmethanamine according to claim 4, wherein: the second organic solvent is one or the combination of more than two of methanol, ethanol, n-propanol, isopropanol, water, ethyl acetate, propyl acetate, acetone, butanone, dioxane, 2-methyl-tetrahydrofuran, dichloromethane, chlorobenzene and ethylene glycol dimethyl ether.
8. The process for producing (3R) -tetrahydro-3-furanmethanamine according to claim 5, wherein: the third organic solvent is one or the combination of more than two of methanol, ethanol, n-propanol, isopropanol, water, ethyl acetate, propyl acetate, acetone, butanone, dioxane, 2-methyl-tetrahydrofuran, dichloromethane, chlorobenzene and ethylene glycol dimethyl ether.
9. The process for producing (3R) -tetrahydro-3-furanmethanamine according to claim 1, wherein: the number of recrystallizations was 2.
10. The process for producing (3R) -tetrahydro-3-furanmethanamine according to claim 1, wherein: the temperature of the process of adding the resolving agent and separating out the solid after stirring is 0-100 ℃.
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| CN102603592A (en) * | 2012-02-20 | 2012-07-25 | 上海应用技术学院 | Preparation method for (R)-1-benzyl-3-aminopyrrolidine and (S)-1-benzyl-3-aminopyrrolidine |
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| EP1958666A1 (en) * | 2007-02-13 | 2008-08-20 | Speedel Experimenta AG | Heterocyclic-substituted alkanamides as therapeutic compounds |
| CN102603592A (en) * | 2012-02-20 | 2012-07-25 | 上海应用技术学院 | Preparation method for (R)-1-benzyl-3-aminopyrrolidine and (S)-1-benzyl-3-aminopyrrolidine |
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